LncRNA SNHG11 facilitates tumor metastasis by interacting with and stabilizing HIF-1\u03b1

Lin Huan,Shenglin Huang,Linguo Xu,Xianghuo He,Qifeng Wang,Linhui Liang,Tianan Guo,Yanfang Liu,Yangjun Wu,Ye Xu

doi:10.1038/s41388-020-01512-8

Abstract

Epigenetic alteration is one of the hallmarks of colorectal cancer (CRC). Many driver genes are regulated by DNA methylation in CRC. However, the role of DNA methylation regulating lncRNAs remain elusive. Here, we identify that SNHG11 (small nucleolar RNA host gene 11) is upregulated by promotor hypomethylation in CRC and is associated with poor prognosis in CRC patients. SNHG11 can promote CRC cell migration and metastasis under hypoxia. Interestingly, the DNA-binding motif of SNHG11 is similar to that of HIF-1α. In addition, SNHG11-associated genes are enriched with members of the HIF-1 signaling pathway in CRC. Mechanistically, SNHG11 binds to the pVHLrecognition sites on HIF-1α, thus blocking the interaction of pVHL with HIF-1α and preventing its ubiquitination and degradation. Moreover, SNHG11 upregulates the expression of HIF-1α target genes, i.e., AK4, ENO1, HK2, and Twist1. Notably, SNHG11 can bind to the HRE sites in the promoter of these genes and increase their transcription. In summary, these results identify a SNHG11/ HIF-1α axis that plays a pivotal role in tumor invasion and metastasis.

Highlights

These authors contributed : Linguo Xu, Lin Huan
The function of a long noncoding RNAs (lncRNAs) is dependent on its subcellular localization, so knowing the localization of lncRNAs enables the prediction of their biological function [19]
By analyzing RNA-seq data from the lncATLAS database [20], we determined the subcellular localization of the 18 candidate lncRNAs that were negatively correlated with DNA methylation in The Cancer Genome Atlas (TCGA)-COAD and found that 7 of them localized in the nucleus (Supplementary Fig. 1B)

Summary

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Expression of a group pf genes can be regulated by DNA methylation in the initiation and progression of CRC [3]. Emerging studies have indicated that RNAs are crucial for the function of transcription factors and chromatin regulators [11,12,13,14]. Deletion of RNA binding sites in CTCF significantly dampens the ability of CTCF to form chromatin loops [17]. These findings indicate that the crosstalk between lncRNAs and TF/ chromatin regulators is crucial for the chromatin structure and gene transcription program. SNHG11 enhanced the transcriptional activity of HIF-1α and promoted CRC progression

Results

Discussion

Materials and methods

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